SPRING 2001

Fatty Acid Synthase Inhibitor Leads to Dramatic Weight Loss in Mice

Researchers at the Johns Hopkins University in Baltimore, Maryland have developed a synthetic enzyme inhibitor that causes mice to consume up to 90 percent less food, leading to profound weight loss. The research team, led by Francis P. Kuhajda, M.D., of the Department of Pathology at the Johns Hopkins University School of Medicine, believes that the discovery may represent a new therapeutic approach to the control of appetite and body weight.

Central to the premise is fatty acid synthase (FAS), an enzyme system for turning carbohydrates into the building blocks of fat. Fatty acids are simple lipids that furnish most of the calories from dietary fat. The body is capable of synthesizing its own fatty acids during energy surplus, when excess physiological fuels are channeled into energy storage. After the discovery in the early 1990s that cancer cells use the enzyme system to produce their own fat for fuel, the researchers synthesized an FAS inhibitor known as C75 to block this process. When C75 is administered to mice, they “drop their weight like a stone,” according to Dr. Kuhajda, “losing 25 percent of their body mass in a couple of days” without any apparent side effects.

The researchers found that the action of neuropeptide Y (NPY), a brain chemical that promotes feeding, contributes to loss of appetite in C75-treated mice. Normally, levels of NPY increase during fasting in mice. In the C75-treated mice, however, NPY levels decreased during fasting. This led the researchers to conclude that C75 inhibits feeding, at least in part, by blocking the increase in NPY levels with fasting.

To determine whether the weight loss was entirely due to suppressed feeding, the researchers compared C75 treatment-induced weight loss to that due to fasting alone. C75-treated mice lost 45 percent more weight than fasting mice. Because fasting normally leads to a slowing of metabolism, the more dramatic weight loss in C75-treated mice suggests that C75 blocks the compensatory decrease in energy use that occurs during weight loss.

Inhibition of FAS by C75 results in increases in malonyl-coenzyme A (malonyl-CoA), one of the primary building blocks of fatty acids. The researchers suggest that high levels of malonyl-CoA may mimic fatty acid synthesis and thus the fed state, acting as the important signal that suppresses feeding and maintains normal levels of metabolism. Regulation of malonyl-CoA levels may therefore be a key factor in control of appetite, basal metabolism, and energy expenditure.

In addition to their conclusion that FAS may be an important therapeutic target for the treatment of obesity, the researchers continue to pursue C75 as a possible treatment for cancer. The study, partially funded by the National Institute of Diabetes and Digestive and Kidney Diseases, appears in the June 30, 2000 issue of Science. The full report is available to subscribers online at www.sciencemag.org. s